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  • Print publication year: 2011
  • Online publication date: September 2011

24 - Hypocretinergic system: role in REM-sleep regulation

from Section IV - Neuroanatomy and neurochemistry



The hypocretins (HCRTs) are two hypothalamic peptides that have been implicated in a variety of functions including the regulation of behavioral arousal. In the brain, HCRT-expressing neurons are localized within the perifornical-lateral hypothalamic area, where they are intermingled with various other neuronal groups, including GABAergic, glutamatergic, and melanin-concentrating hormone containing neurons. Hypocretin neurons are active during behavioral arousal and are quiet during non-REM and REM sleep. Deficiency of HCRTergic signaling is linked to the symptoms of narcolepsy in humans, dogs, and rodents. Narcolepsy is a debilitating sleep disorder characterized by excessive daytime sleepiness, disrupted nighttime sleep, sleep-onset REM sleep, and sudden loss of muscle tone during waking (cataplexy). Hypocretin neurons project extensively to brain structures, especially to those that are involved in arousal and motor control as well as receive extensive inputs from areas regulating emotions, autonomic tone, appetite, circadian rhythms, and sleep–wake behavior. Therefore, HCRT neurons are well positioned to integrate a variety of interoceptive and homeostatic signals to increase behavioral arousal and suppress REM sleep and its atonia. This chapter provides a brief review of the HCRTergic system, its interactions with other neuronal systems involved in sleep–wake regulation, and the neuronal circuitry and the potential mechanism(s) by which the HCRTergic system promotes behavioral arousal and suppresses REM sleep and its muscle atonia.

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Adamantidis, A. R., Zhang, F., Aravanis, A. M., Deisseroth, K. & de Lecea, L. (2007) Neural substrates of awakening probed with optogenetic control of hypocretin neurons. Nature 450: –4.
Alam, M. N., Gong, H., Alam, T., Jaganath, R., McGinty, D. & Szymusiak, R. (2002) Sleep–waking discharge patterns of neurons recorded in the rat perifornical lateral hypothalamic area. J Physiol 538: –31.
Alam, M. N., Kumar, S., Bashir, T. . (2005) GABA-mediated control of hypocretin- but not melanin-concentrating hormone immunoreactive neurones during sleep in rats. J Physiol 563: –82.
Chemelli, R. M., Willie, J. T., Sinton, C. M. . (1999) Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 98: –51.
de Lecea, L., Kilduff, T. S., Peyron, C. . (1998) The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc Natl Acad Sci U S A 95: –7.
Eggermann, E., Bayer, L., Serafin, M. . (2003) The wake-promoting hypocretin-orexin neurons are in an intrinsic state of membrane depolarization. J Neurosci 23: –62.
Eriksson, K. S., Sergeeva, O. A., Haas, H. L. & Selbach, O. (2010) Orexins/hypocretins and aminergic systems. Acta Physiol (Oxf) 198: 263–75.
Fort, P., Bassetti, C. L. & Luppi, P. H. (2009) Alternating vigilance states: new insights regarding neuronal networks and mechanisms. Eur J Neurosci 29: –53.
Gallopin, T., Fort, P., Eggermann, E., . (2000) Identification of sleep-promoting neurons in vitro. Nature 404: –5.
Gong, H., McGinty, D., Guzman-Marin, R., . (2004) Activation of c-fos in GABAergic neurones in the preoptic area during sleep and in response to sleep deprivation. J Physiol 556: –46.
Hassani, O. K., Lee, M. G. & Jones, B. E. (2009) Melanin-concentrating hormone neurons discharge in a reciprocal manner to orexin neurons across the sleep–wake cycle. Proc Natl Acad Sci U S A 106: –22.
Henny, P. & Jones, B. E. (2006) Innervation of orexin/hypocretin neurons by GABAergic, glutamatergic or cholinergic basal forebrain terminals evidenced by immunostaining for presynaptic vesicular transporter and postsynaptic scaffolding proteins. J Comp Neurol 499: –61.
Huang, Z. L., Qu, W. M., Li, W. D. . (2001) Arousal effect of orexin A depends on activation of the histaminergic system. Proc Natl Acad Sci U S A 98: –70.
Jones, B. E. (2008) Modulation of cortical activation and behavioral arousal by cholinergic and orexinergic systems. Ann N Y Acad Sci 1129: –34.
Kukkonen, J. P., Holmqvist, T., Ammoun, S. & Akerman, K. E. (2002) Functions of the orexinergic/hypocretinergic system. Am J Physiol Cell Physiol 283: –91.
Kumar, S., Szymusiak, R., Bashir, T. . (2008) Inactivation of median preoptic nucleus causes c-Fos expression in hypocretin- and serotonin-containing neurons in anesthetized rat. Brain Res 1234: –77.
Kumar, S., Szymusiak, R., Methippara, M. M. . (2005) GABAergic and glutamatergic neurons in the perifornical lateral hypothalamic area exhibit differential Fos expression after sleep deprivation vs. recovery sleep. Sleep 29: .
Lee, M. G., Hassani, O. K. & Jones, B. E. (2005) Discharge of identified orexin/hypocretin neurons across the sleep–waking cycle. J Neurosci 25: –20.
Li, Y., Gao, X. B., Sakurai, T. & van den Pol, A. N. (2002) Hypocretin/Orexin excites hypocretin neurons via a local glutamate neuron: a potential mechanism for orchestrating the hypothalamic arousal system. Neuron 36: –81.
Lin, L., Faraco, J., Li, R. . (1999) The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell 98: –76.
Liu, Z. W. & Gao, X. B. (2007) Adenosine inhibits activity of hypocretin/orexin neurons by the A1 receptor in the lateral hypothalamus: a possible sleep-promoting effect. J Neurophysiol 97: –48.
Lu, J., Sherman, D., Devor, M. & Saper, C. B. (2006) A putative flip-flop switch for control of REM sleep. Nature 441: –94.
Marcus, J. N., Aschkenasi, C. J., Lee, C. E. . (2001) Differential expression of orexin receptors 1 and 2 in the rat brain. J Comp Neurol 435: –25.
Matsuki, T., Nomiyama, M., Takahira, H. . (2009) Selective loss of GABA(B) receptors in orexin-producing neurons results in disrupted sleep/wakefulness architecture. Proc Natl Acad Sci U S A 106: –64.
McCarley, R.W. (2007) Neurobiology of REM and NREM sleep. Sleep Med 8: –30.
Mileykovskiy, B. Y., Kiyashchenko, L. I. & Siegel, J. M. (2005) Behavioral correlates of activity in identified hypocretin/orexin neurons. Neuron 46: –98.
Modirrousta, M., Mainville, L. & Jones, B. E. (2005) Orexin and MCH neurons express c-Fos differently after sleep deprivation vs. recovery and bear different adrenergic receptors. Eur J Neurosci 21: –16.
Mori, T., Ito, S., Kuwaki, T., Yanagisawa, M. & Sawaguchi, T. (2009)Monoaminergic neuronal changes in orexin deficient mice. Neuropharmacology.
Nishino, S., Okuro, M., Kotorii, N. . (2010)Hypocretin/orexin and narcolepsy: new basic and clinical insights, Acta Physiol (Oxf) 198: 209–22.
Ohno, K. & Sakurai, T. (2008) Orexin neuronal circuitry: role in the regulation of sleep and wakefulness. Front Neuroendocrinol 29: –87.
Peyron, C., Faraco, J., Rogers, , . (2000) A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nat Med 6: –7.
Peyron, C., Tighe, D. K., van den Pol, A. N., . (1998) Neurons containing hypocretin (orexin) project to multiple neuronal systems. J Neurosci 18: –10,015.
Sakurai, T., Amemiya, A., Ishii, M. . (1998) Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92: –85.
Sakurai, T., Nagata, R., Yamanaka, A. . (2005) Input of orexin/hypocretin neurons revealed by a genetically encoded tracer in mice. Neuron 46: –308.
Saper, C. B., Cano, G. & Scammell, T. E. (2005) Homeostatic, circadian, and emotional regulation of sleep. J Comp Neurol 493: –8.
Siegel, J. M. (2004a) Hypocretin (orexin): role in normal behavior and neuropathology. Ann Rev Psychol 55: –48.
Siegel, J.M. (2004b) The neurotransmitters of sleep, J Clin Psychiatry, 65 Suppl 16: –7.
Suntsova, N., Guzman-Marin, R., Kumar, S. . (2007) The median preoptic nucleus reciprocally modulates activity of arousal-related and sleep-related neurons in the perifornical lateral hypothalamus. J Neurosci 27: –30.
Suntsova, N., Szymusiak, R., Alam, M. N., Guzman-Marin, R. & McGinty, D. (2002) Sleep–waking discharge patterns of median preoptic nucleus neurons in rats. J Physiol 543: –77.
Szymusiak, R. & McGinty, D. (2008) Hypothalamic regulation of sleep and arousal. Ann N Y Acad Sci 1129: –86.
Thakkar, M. M., Engemann, S. C., Walsh, K. M. & Sahota, P. K. (2008) Adenosine and the homeostatic control of sleep: effects of A1 receptor blockade in the perifornical lateral hypothalamus on sleep–wakefulness. Neuroscience 153: –80.
Thakkar, M. M., Ramesh, V., Cape, E. G. . (1999) REM sleep enhancement and behavioral cataplexy following orexin (hypocretin)-II receptor antisense perfusion in the pontine reticular formation. Sleep Res Online 2: –20.
Thannickal, T. C., Moore, R. Y., Nienhuis, R. . (2000) Reduced number of hypocretin neurons in human narcolepsy. Neuron 27: –74.
Torrealba, F., Yanagisawa, M. & Saper, C. B. (2003) Colocalization of orexin a and glutamate immunoreactivity in axon terminals in the tuberomammillary nucleus in rats. Neuroscience 119: –44.
Trivedi, P., Yu, H., MacNeil, D. J., Van der Ploeg, L. H. & Guan, X. M. (1998) Distribution of orexin receptor mRNA in the rat brain. FEBS Lett 438: –5.
Uschakov, A., Gong, H., McGinty, D. & Szymusiak, R. (2006) Sleep-active neurons in the preoptic area project to the hypothalamic paraventricular nucleus and perifornical lateral hypothalamus. Eur J Neurosci 23: –96.
Verret, L., Goutagny, R., Fort, P. . (2003) A role of melanin-concentrating hormone producing neurons in the central regulation of paradoxical sleep. BMC Neurosci 4: .
Yoshida, K., McCormack, S., Espana, R. A., Crocker, A. & Scammell, T. E. (2006) Afferents to the orexin neurons of the rat brain. J Comp Neurol 494: –61.